Eukaryotic cells respond to DNA damaging events, such as gamma-irradiation exposure, by halting cell cycle progression, and activating DNA repair mechanisms. In the case of irreparable DNA damage, cells also respond by initiating programmed cell death or apoptosis. Not surprisingly, defects in these responses often result in gene mutation, chromosomal aberrations, which in turn can lead to malignancy. Sitting at the top of the signaling networks induced by IR, and orchestrating these responses is the product of the gene that is mutated in Ataxia Telangiectasia (ATM). Studies from the principal investigator's laboratory determined that, despite its structural similarity to lipid kinases, ATM displays protein kinase activity. Further, when activated by ionizing radiation (IR), ATM activates the c-Abl tyrosine kinase via direct phosphorylation. ATM-activated Abl subsequently phosphorylates RNA polymerase II (RNAP II) on its C-terminal repeated domain to modulate transcription of genes required for DNA damage responses. The major objective of this study is to extend our ongoing research focused on elucidating the functional significance of ATM to Abl to RNAP II signaling in genome damage response. To accomplish the objective, the proposed specific aims are: a) determine the role of ATM-activated Abl in cell cycle checkpoint activation, b) determine the role of ATM-activated Abl in JR-induced apoptosis and DNA repair responses, and c) decipher the functional significance of RNAP II tyrosine phosphorylation in genome damage responses.